全文获取类型
收费全文 | 596篇 |
免费 | 52篇 |
国内免费 | 1篇 |
出版年
2023年 | 13篇 |
2022年 | 8篇 |
2021年 | 28篇 |
2020年 | 23篇 |
2019年 | 32篇 |
2018年 | 31篇 |
2017年 | 23篇 |
2016年 | 25篇 |
2015年 | 50篇 |
2014年 | 38篇 |
2013年 | 42篇 |
2012年 | 35篇 |
2011年 | 37篇 |
2010年 | 21篇 |
2009年 | 25篇 |
2008年 | 19篇 |
2007年 | 32篇 |
2006年 | 27篇 |
2005年 | 13篇 |
2004年 | 18篇 |
2003年 | 18篇 |
2002年 | 15篇 |
2001年 | 5篇 |
1999年 | 2篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1994年 | 5篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1989年 | 1篇 |
1987年 | 1篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 1篇 |
1981年 | 3篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1973年 | 2篇 |
1969年 | 2篇 |
1968年 | 2篇 |
1967年 | 1篇 |
1966年 | 2篇 |
1965年 | 2篇 |
1963年 | 1篇 |
排序方式: 共有649条查询结果,搜索用时 593 毫秒
401.
Syeda S. Hassan Muhammad Akram Elizabeth C. King Hazel M. Dockrell Jacqueline M. Cliff 《PloS one》2015,10(9)
Background
The PD-1 axis is a cell intrinsic immunoregulatory pathway that mediates T cell exhaustion in chronic infection particularly in some viral infections. We hypothesized that PD-1, PD-L1 and PD-L2 would be highly expressed in untreated tuberculosis patients compared to controls due to their chronic infection and would decrease with successful TB treatment.Materials and Methods
Untreated tuberculosis patients (n = 26) were recruited at diagnosis and followed up during treatment. Household contacts (n = 24) were recruited to establish baseline differences. Blood gene expression ex vivo was investigated using qRT-PCR. Flow cytometry was performed to establish protein expression patterns.Results
PD-L1 gene expression was found to be elevated in active TB disease; however, this was not observed for PD-1 or PD-L2. The intensive phase of TB treatment was associated with a significant decline in PD-1, PD-L1 and PD-L2 gene expression. PD-1 protein expression on the surface of NK cells, CD8+ and CD4+ T cells was similar in patients with active TB disease compared to controls but declined with successful TB treatment, with the greatest decline occurring on the NK cells followed by CD8+ T cells and then CD4+ T cells. Granzyme B/PD-1 co-expression declined with successful intensive phase treatment.Conclusion
Modulation of PD-1/PD-L1 pathway through TB treatment indicates changes in the peripheral T cell response caused by live Mycobacterium tuberculosis (Mtb) followed by the response to dead bacilli, antigen-release and immuno-pathology resolution. The PD-1 axis could be a host drug target for immunomodulatory treatments in the future. 相似文献402.
Bruno Maranhao Pooja Biswas Alexander D. H. Gottsch Mili Navani Muhammad Asif Naeem John Suk Justin Chu Sheen N. Khan Rachel Poleman Javed Akram Sheikh Riazuddin Pauline Lee S. Amer Riazuddin J. Fielding Hejtmancik Radha Ayyagari 《PloS one》2015,10(9)
Purpose
To define the molecular basis of retinal degeneration in consanguineous Pakistani pedigrees with early onset retinal degeneration.Methods
A cohort of 277 individuals representing 26 pedigrees from the Punjab province of Pakistan was analyzed. Exomes were captured with commercial kits and sequenced on an Illumina HiSeq 2500. Candidate variants were identified using standard tools and analyzed using exomeSuite to detect all potentially pathogenic changes in genes implicated in retinal degeneration. Segregation analysis was performed by dideoxy sequencing and novel variants were additionally investigated for their presence in ethnicity-matched controls.Results
We identified a total of nine causal mutations, including six novel variants in RPE65, LCA5, USH2A, CNGB1, FAM161A, CERKL and GUCY2D as the underlying cause of inherited retinal degenerations in 13 of 26 pedigrees. In addition to the causal variants, a total of 200 variants each observed in five or more unrelated pedigrees investigated in this study that were absent from the dbSNP, HapMap, 1000 Genomes, NHLBI ESP6500, and ExAC databases were identified, suggesting that they are common in, and unique to the Pakistani population.Conclusions
We identified causal mutations associated with retinal degeneration in nearly half of the pedigrees investigated in this study through next generation whole exome sequencing. All novel variants detected in this study through exome sequencing have been cataloged providing a reference database of variants common in, and unique to the Pakistani population. 相似文献403.
Background
Recent outbreaks of cutaneous leishmaniasis make the disease a public health concern in Punjab, Pakistan. The knowledge of how the population perceives the disease and its vector is essential in order to design an effective management strategy, but such studies are rare in Pakistan.Methodology/Principal Findings
The present study was based on a cross-sectional self-administered survey comprising 250 household samples collected from five localities including Bhawalpur, Multan, Jhang, Faisalabad and Lahore. The results revealed that the respondents had a poor knowledge of the vector and disease. Few of the respondents were aware about the identification of sand flies, their breeding place, biting time, transmission of leishmaniasis and control measures. Skin infection and sandflies as the main disease symptom and vector of the disease, respectively, were known to some of the respondents. Some believed that summer was the main peak incidence of the disease and it could be transmitted from man to man via contact. However, most of the respondents believed that the disease could be cured. Admission to hospitals, cleanliness and use of bed nets were the treatment measures for the disease in suspected patients, whereas some thought that the use of bed nets could be helpful in preventing leishmaniasis infection.Conclusions/Significance
Poor knowledge of the disease and its vector in the study population emphasize the need to initiate health education and awareness campaigns to minimize the risks of cutaneous leishmaniasis outbreaks in the future. 相似文献404.
Dan Cao Zeqi Su Wenwen Wang Huihui Wu Xing Liu Saima Akram Bo Qin Jiajia Zhou Xiaoxuan Zhuang Gregory Adams Changjiang Jin Xiwei Wang Lifang Liu Donald L. Hill Dongmei Wang Xia Ding Xuebiao Yao 《The Journal of biological chemistry》2015,290(39):23766-23780
Cell migration is orchestrated by dynamic interaction of microtubules with the plasma membrane cortex. However, the regulatory mechanisms underlying the cortical actin cytoskeleton and microtubule dynamics are less characterized. Our earlier study showed that small GTPase-activating proteins, IQGAPs, regulate polarized secretion in epithelial cells (1). Here, we show that IQGAP1 links dynamic microtubules to steer cell migration via interacting with the plus-end tracking protein, SKAP. Biochemical characterizations revealed that IQGAP1 and SKAP form a cognate complex and that their binding interfaces map to the WWIQ motif and the C-terminal of SKAP, respectively. The WWIQ peptide disrupts the biochemical interaction between IQGAP1 and SKAP in vitro, and perturbation of the IQGAP1-SKAP interaction in vivo using a membrane-permeable TAT-WWIQ peptide results in inhibition of directional cell migration elicited by EGF. Mechanistically, the N-terminal of SKAP binds to EB1, and its C terminus binds to IQGAP1 in migrating cells. Thus, we reason that a novel IQGAP1 complex orchestrates directional cell migration via coupling dynamic microtubule plus-ends to the cell cortex. 相似文献
405.
Deoxycytidylate deaminase is unique within the zinc-dependent cytidine deaminase family as being allosterically regulated, activated by dCTP, and inhibited by dTTP. Here we present the first crystal structure of a dTTP-bound deoxycytidylate deaminase from the bacteriophage S-TIM5, confirming that this inhibitor binds to the same site as the dCTP activator. The molecular details of this structure, complemented by structures apo- and dCMP-bound, provide insights into the allosteric mechanism. Although the positioning of the nucleoside moiety of dTTP is almost identical to that previously described for dCTP, protonation of N3 in deoxythymidine and not deoxycytidine would facilitate hydrogen bonding of dTTP but not dCTP and may result in a higher affinity of dTTP to the allosteric site conferring its inhibitory activity. Further the functional group on C4 (O in dTTP and NH2 in dCTP) makes interactions with nonconserved protein residues preceding the allosteric motif, and the relative strength of binding to these residues appears to correspond to the potency of dTTP inhibition. The active sites of these structures are also uniquely occupied by dTMP and dCMP resolving aspects of substrate specificity. The methyl group of dTMP apparently clashes with a highly conserved tyrosine residue, preventing the formation of a correct base stacking shown to be imperative for deamination activity. The relevance of these findings to the wider zinc-dependent cytidine deaminase family is also discussed. 相似文献
406.
Characterisation of full genome of Dolichos yellow mosaic virus based on sequence comparison,genetic recombination and phylogenetic relationship
下载免费PDF全文
![点击此处可从《The Annals of applied biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
M. Akram Naimuddin A.K. Agnihotri S. Gupta N.P. Singh 《The Annals of applied biology》2015,167(3):354-363
Yellow mosaic disease (YMD) is one of the most important diseases affecting different leguminous crops and causes significant yield losses in Indian sub‐continent. Eight different bipartite begomovirus species are known to cause YMD in more than 10 leguminous crops. These species are collectively known as legume yellow mosaic viruses (LYMVs), and their full genomes have been characterised except for Dolichos yellow mosaic virus (DoYMV). In this study, full genome of DoYMV isolate (KJ481204 and KJ481205) infecting dolichos has been characterised. The DNA‐A of DoYMV consists of 2761 nucleotides and DNA‐B of 2733 nucleotides with a genome organisation typical of Old World bipartite begomoviruses. Nucleotide identity of DNA‐B (KJ481205) of DoYMV with DNA‐B of other legumoviruses was 57.5–61.0%. Both components contain a nonanucleotide and conserved inverted repeat sequences with the potential to form a stem‐loop. Nucleotide identity of common region of DoYMV was 90.3%, above the threshold nucleotide identity (>85%) for considering a DNA‐B molecule as cognate of DNA‐A of a begomovirus. Four recombination events in DNA‐A and two in DNA‐B of DoYMV isolate were detected. Mungbean yellow mosaic virus, Rhynchosia yellow mosaic virus and Horsegram yellow mosaic virus were identified as probable parents. 相似文献
407.
408.
Sadaf G. Sepanlou Reza Malekzadeh Hossein Poustchi Maryam Sharafkhah Saeed Ghodsi Fatemeh Malekzadeh Arash Etemadi Akram Pourshams Paul D. Pharoah Christian C. Abnet Paul Brennan Paolo Boffetta Sanford M. Dawsey Farin Kamangar 《PloS one》2015,10(5)
BackgroundCardiovascular diseases (CVD) are becoming major causes of death in developing countries. Risk scoring systems for CVD are needed to prioritize allocation of limited resources. Most of these risk score algorithms have been based on a long array of risk factors including blood markers of lipids. However, risk scoring systems that solely use office-based data, not including laboratory markers, may be advantageous. In the current analysis, we validated the office-based Framingham risk scoring system in Iran.MethodsThe study used data from the Golestan Cohort in North-East of Iran. The following risk factors were used in the development of the risk scoring method: sex, age, body mass index, systolic blood pressure, hypertension treatment, current smoking, and diabetes. Cardiovascular risk functions for prediction of 10-year risk of fatal CVDs were developed.ResultsA total of 46,674 participants free of CVD at baseline were included. Predictive value of estimated risks was examined. The resulting Area Under the ROC Curve (AUC) was 0.774 (95% CI: 0.762-0.787) in all participants, 0.772 (95% CI: 0.753-0.791) in women, and 0.763 (95% CI: 0.747-0.779) in men. AUC was higher in urban areas (0.790, 95% CI: 0.766-0.815). The predicted and observed risks of fatal CVD were similar in women. However, in men, predicted probabilities were higher than observed.ConclusionThe AUC in the current study is comparable to results of previous studies while lipid profile was replaced by body mass index to develop an office-based scoring system. This scoring algorithm is capable of discriminating individuals at high risk versus low risk of fatal CVD. 相似文献
409.
Huda Kaatabi Abdullah Omar Bamosa Ahmed Badar Abdulmohsen Al-Elq Bodour Abou-Hozaifa Fatma Lebda Akram Al-Khadra Sameeh Al-Almaie 《PloS one》2015,10(2)
Methods114 type 2 diabetic patients on standard oral hypoglycemic drugs were assigned into 2 groups by convenience. The control group (n = 57) received activated charcoal as placebo and NS group (n = 57) received 2g NS, daily, for one year in addition to their standard medications. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), C- peptide, total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), glutathione and thiobarbituric acid reactive substances (TBARS) at the baseline, and every 3 months thereafter were determined. Insulin resistance and β-cell activity were calculated using HOMA 2 calculator.ResultsComparison between the two groups showed a significant drop in FBG (from 180±5.75 to 180±5.59 in control Vs from 195±6.57 to 172 ±5.83 in NS group), HbA1c (from 8.2±0.12 to 8.5±0.14 in control VS from 8.6±0.13 to 8.2±0.14 in NS group), and TBARS (from 48.3±6.89 to 52.9 ±5.82 in control VS from 54.1±4.64 to 41.9 ±3.16 in NS group), in addition to a significant elevation in TAC, SOD and glutathione in NS patients compared to controls. In NS group, insulin resistance was significantly lower, while β-cell activity was significantly higher than the baseline values during the whole treatment period.ConclusionLong term supplementation with Nigella sativa improves glucose homeostasis and enhances antioxidant defense system in type 2 diabetic patients treated with oral hypoglycemic drugs.
Trial Registration
Clinical Trials Registry-India (CTRI) CTRI/2013/06/003781 相似文献410.